The purpose of our studies is to develop new methods of gene transfer into hematopoietic stem cells using the genetic disease leukocyte adhesion deficiency or LAD as a model. For these studies we are using the canine form of LAD first to identify the number of hematopoietic stem cells required to reverse the disease phenotype and second, to test new retroviral vectors, conditioning regimens, and immunosuppressive agents required to enable sufficient numbers of gene modified hematopoietic stem cells to engraft and reverse the disease phenotype. The canine form of this disease is an optimal model for these studies since: a) the defect involves a membrane receptor on the surface of leukocytes, flow cytometry allows fascile detection and analysis of the number of gene corrected cells, b) low levels of gene corrected cells are likely to result in reversal of the disease phenotype, and c) studies in the canine model have been predictive of success in humans in the field of hematopoietic stem cell biology in that the background genetic heterogeneity between non-inbred dogs is similar to the genetic diversity of affected human populations, and d) the presence of a human counterpart to CLAD, namely LAD, allows the results from the animal model to be directly extrapolated to humans. We have now generated affected CLAD animals. CLAD animals with a matched donor are receiving non-myeloablative, allogeneic transplants to establish the number of CD18 positive cells required to reverse the disease phenotype. Those animals without donors will receive infusions of autologous, gene-corrected cells. These studies should provide the basis for future clinical approaches to LAD.